Reviewed, UniProtKB/Swiss-Prot P04062 (GLCM_HUMAN)

Names and origin

Protein names

Recommended name:
    Glucosylceramidase
    EC=3.2.1.45
Alternative name(s):
    Beta-glucocerebrosidase
    Acid beta-glucosidase
    D-glucosyl-N-acylsphingosine glucohydrolase
    Alglucerase
    Imiglucerase

Gene names

Name:	GBA
Synonyms:	GC, GLUC

Organism

Homo sapiens (Human)

Taxonomic identifier

9606 [NCBI]

Taxonomic lineage

Eukaryota › Metazoa › Chordata › Craniata › Vertebrata › Euteleostomi › Mammalia › Eutheria › Euarchontoglires › Primates › Haplorrhini › Catarrhini › Hominidae › Homo

Protein attributes

Sequence length	536 AA.
Sequence status	Complete.
Sequence processing	The displayed sequence is further processed into a mature form.
Protein existence	Evidence at protein level.

General annotation (Comments)

Catalytic activity	D-glucosyl-N-acylsphingosine + H(2)O = D-glucose + N-acylsphingosine.
Enzyme regulation	Requires saposin-C and anionic phospholipids for activity.
Subunit structure	Interacts with saposin-C.
Subcellular location	Lysosome membrane; Peripheral membrane protein; Lumenal side. Note= Interaction with saposin-C promotes membrane association.
Involvement in disease	Defects in GBA are the cause of Gaucher disease (GD) [MIM:230800]; also known as glucocerebrosidase deficiency. GD is the most prevalent lysosomal storage disease, characterized by accumulation of glucosylceramide in the reticulo-endothelial system. Different clinical forms are recognized depending on the presence (neuronopathic forms) or absence of central nervous system involvement, severity and age of onset. Defects in GBA are the cause of Gaucher disease type 1 (GD1) [MIM:230800]; also known as adult non-neuronopathic Gaucher disease. GD1 is characterized by hepatosplenomegaly with consequent anemia and thrombopenia, and bone involvement. The central nervous system is not involved. Defects in GBA are the cause of Gaucher disease type 2 (GD2) [MIM:230900]; also known as acute neuronopathic. GD2 is the most severe form and is universally progressive and fatal. It manifests soon after birth, with death generally occurring before patients reach two years of age. Defects in GBA are the cause of Gaucher disease type 3 (GD3) [MIM:231000]; also known as subacute neuronopathic. GD3 has central nervous manifestations. Defects in GBA are the cause of Gaucher disease type 3C [MIM:231005]; also known as pseudo-Gaucher disease or Gaucher-like disease. Defects in GBA are the cause of perinatal lethal Gaucher disease [MIM:608013]. It is a distinct form of Gaucher disease type 2, characterized by fetal onset. Hydrops fetalis, in utero fetal death and neonatal distress are prominent features. When hydrops is absent, neurologic involvement begins in the first week and leads to death within 3 months. Hepatosplenomegaly is a major sign, and is associated with ichthyosis, arthrogryposis, and facial dysmorphism. Perinatal lethal Gaucher disease is associated with non-immune hydrops fetalis [MIM:236750]. Hydrops fetalis is a generalized edema of the fetus with fluid accumulation in the body cavities. Defects in GBA may be a risk factor in the development of Parkinson disease (PD) [MIM:168600]. Simultaneous occurrence of Parkinson disease and Gaucher disease is marked by atypical parkinsonism generally presenting by the fourth through sixth decades of life. The combination progresses inexorably and is refractory to conventional anti-Parkinson therapy.
Pharmaceutical use	Available under the names Ceredase and Cerezyme (Genzyme). Used to treat Gaucher's disease.
Sequence similarities	Belongs to the glycosyl hydrolase 30 family.

Ontologies

Keywords
Biological process	Lipid metabolism Sphingolipid metabolism
Cellular component	Lysosome Membrane
Coding sequence diversity	Alternative initiation Alternative splicing Polymorphism
Disease	Disease mutation Gaucher disease Ichthyosis
Domain	Signal
Molecular function	Glycosidase Hydrolase
PTM	Glycoprotein
Technical term	3D-structure Direct protein sequencing Pharmaceutical
Gene Ontology (GO)
Biological process	carbohydrate metabolic process Inferred from electronic annotation. Source: InterPro lysosome organization Inferred from electronic annotation. Source: InterPro sphingolipid metabolic process Inferred from electronic annotation. Source: InterPro
Cellular component	lysosomal membrane Inferred from electronic annotation. Source: UniProtKB-SubCell
Molecular function	cation binding Inferred from electronic annotation. Source: InterPro glucosylceramidase activity Inferred from electronic annotation. Source: InterPro protein binding Inferred from physical interaction. Source: IntAct
Complete GO annotation...

Binary interactions

With	Entry	#Exp.	IntAct	Notes
Scarb2	O35114	1	EBI-1564609,EBI-1564519	From a different organism.

Alternative products

This entry describes 3 isoforms produced by alternative splicing and alternative initiation. [Align] [Select]

Isoform Long (identifier: P04062-1)

This isoform has been chosen as the 'canonical' sequence. All positional information in this entry refers to it. This is also the sequence that appears in the downloadable versions of the entry.

Notes: Has a 39 residue signal sequence. The upstream initiation site produces two to three times as much protein as does the downstream initiation codon.

Isoform Short (identifier: P04062-2)

The sequence of this isoform differs from the canonical sequence as follows:
     1-20: Missing.

Notes: Has a 19 residue signal sequence.

Isoform 3 (identifier: P04062-3)

The sequence of this isoform differs from the canonical sequence as follows:
     1-161: Missing.
     422-423: LA → PS
     425-536: Missing.

Notes: Produced by alternative splicing.

Sequence annotation (Features)

	Feature key	Position(s)	Length	Description	Graphical view	Feature identifier
Molecule processing
	Signal peptide	1 – 39	39	In isoform Long
	Signal peptide	21 – 39	19	In isoform Short
	Chain	40 – 536	497	Glucosylceramidase		PRO_0000012177
Sites
	Active site	274	1	Proton donor
	Active site	379	1	Nucleophile
Amino acid modifications
	Glycosylation	58	1	N-linked (GlcNAc...)
	Glycosylation	98	1	N-linked (GlcNAc...)
	Glycosylation	185	1	N-linked (GlcNAc...)
	Glycosylation	309	1	N-linked (GlcNAc...)
	Glycosylation	501	1	N-linked (GlcNAc...) Potential
	Disulfide bond	43 ↔ 55
	Disulfide bond	57 ↔ 62
Natural variations
	Alternative sequence	1 – 161	161	Missing in isoform 3.		VSP_025216
	Alternative sequence	1 – 20	20	Missing in isoform Short.		VSP_018800
	Alternative sequence	422 – 423	2	LA → PS in isoform 3.		VSP_025217
	Alternative sequence	425 – 536	112	Missing in isoform 3.		VSP_025218
	Natural variant	54	1	V → L in GD.		VAR_003255
	Natural variant	55	1	C → S in GD; neuronopathic and perinatal lethal forms; loss of activity.		VAR_032394
	Natural variant	63	1	D → N in GD; type 1; very low activity.		VAR_032395
	Natural variant	76	1	F → V in GD.		VAR_003256
	Natural variant	80	1	E → K in GD; type 2. dbSNP rs3205616.		VAR_009033
	Natural variant	82	1	T → I in GD.		VAR_003257
	Natural variant	85	1	G → E in GD.		VAR_003258
	Natural variant	87	1	R → Q in GD; 20% of normal activity.		VAR_032197
	Natural variant	87	1	R → W in GD; mild. dbSNP rs1141814.		VAR_003259
	Natural variant	92	1	M → T: dbSNP rs3205619.		VAR_032396
	Natural variant	118	1	K → N in GD; mild; 8% of normal activity; increases susceptibility to proteolytic degradation.		VAR_003260
	Natural variant	129	1	A → T in GD.		VAR_032397
	Natural variant	146	1	S → L in GD; type 2.		VAR_009034
	Natural variant	152	1	G → E in GD.		VAR_003261
	Natural variant	156	1	N → D in GD.		VAR_032398
	Natural variant	158	1	I → S in GD; type 1; very low activity.		VAR_032399
	Natural variant	158	1	I → T in GD.		VAR_003262
	Natural variant	159	1	R → Q in GD; type 2; 13% of normal activity.		VAR_003263
	Natural variant	159	1	R → W in GD; severe.		VAR_003264
	Natural variant	161	1	P → L in GD; 16% of normal activity.		VAR_032198
	Natural variant	161	1	P → S in GD; mild.		VAR_003265
	Natural variant	162	1	M → V in GD; loss of activity; increases susceptibility to proteolytic degradation.		VAR_032199
	Natural variant	166	1	D → V in GD; 9% of normal activity; increases susceptibility to proteolytic degradation.		VAR_032200
	Natural variant	170	1	R → C in GD; type 1 and type 2.		VAR_009035
	Natural variant	170	1	R → L in GD.		VAR_009036
	Natural variant	173	1	T → I in GD.		VAR_032400
	Natural variant	173	1	T → P in GD.		VAR_003266
	Natural variant	175	1	A → E in GD.		VAR_032401
	Natural variant	179	1	D → H in GD.		VAR_003267
	Natural variant	196	1	K → Q in GD; severe.		VAR_003268
	Natural variant	198	1	P → L in GD.		VAR_009037
	Natural variant	198	1	P → T in GD.		VAR_032402
	Natural variant	200	1	I → N in GD; 5% of normal activity.		VAR_032201
	Natural variant	200	1	I → S in GD.		VAR_010059
	Natural variant	201	1	H → P in GD.		VAR_032403
	Natural variant	209	1	R → C in GD.		VAR_032404
	Natural variant	209	1	R → P in GD.		VAR_003269
	Natural variant	213	1	L → F in GD; 12% of normal activity.		VAR_032202
	Natural variant	215	1	A → D in GD.		VAR_003270
	Natural variant	217	1	P → S in GD; type 2.		VAR_003271
	Natural variant	221	1	P → L in GD; type 1; very low activity.		VAR_032405
	Natural variant	221	1	P → T in GD.		VAR_003272
	Natural variant	223	1	W → R in GD; gene conversion.		VAR_003273
	Natural variant	224	1	L → F in GD; 4% of normal activity; increases susceptibility to proteolytic degradation.		VAR_032203
	Natural variant	227	1	N → K in GD; gene conversion. dbSNP rs381418.		VAR_003275
	Natural variant	227	1	N → S in GD; type 2. dbSNP rs364897.		VAR_003274
	Natural variant	228	1	G → V in GD.		VAR_010060
	Natural variant	229	1	A → E in GD; type 2.		VAR_009038
	Natural variant	229	1	A → T in GD.		VAR_032406
	Natural variant	230	1	V → E in GD; type 1; very low activity.		VAR_032407
	Natural variant	230	1	V → G in GD; mild; gene conversion. dbSNP rs381427.		VAR_003276
	Natural variant	232	1	G → E in GD; 7% of normal activity.		VAR_032204
	Natural variant	234	1	G → E in GD; severe.		VAR_003277
	Natural variant	234	1	G → W in GD.		VAR_009039
	Natural variant	235	1	S → P in GD; type 2; gene conversion. dbSNP rs1064644.		VAR_003278
	Natural variant	237	1	K → E in GD; severe; loss of activity; increases susceptibility to proteolytic degradation.		VAR_032205
	Natural variant	241	1	G → E in GD.		VAR_010061
	Natural variant	241	1	G → R in GD; type 1 and type 2; gene conversion.		VAR_003279
	Natural variant	244	1	Y → C in GD.		VAR_010062
	Natural variant	251	1	Y → H in GD.		VAR_003280
	Natural variant	252	1	F → I in GD; type 2; gene conversion. dbSNP rs381737.		VAR_003281
	Natural variant	255	1	F → Y in GD; mild.		VAR_003282
	Natural variant	270	1	T → R in GD.		VAR_032408
	Natural variant	276	1	S → P in GD.		VAR_003283
	Natural variant	290	1	F → L in GD; perinatal lethal form.		VAR_032409
	Natural variant	294	1	H → Q in GD; type 1 and type 2.		VAR_009040
	Natural variant	296	1	R → Q in GD; type 2.		VAR_003284
	Natural variant	298	1	F → L in GD; type 2; 4% of normal activity.		VAR_009041